Method for the treatment of
hypertension



United States Patent 3,296,070 METHOD FOR THE TREATMENT OF HYPERTENSION John G. Topliss, East Orange, and Nathan perber, North Caldwell, Ni, assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Feb. 21, 1961, Ser. No. 90,632 7 Claims. (Cl. 167-65) This invention relates to novel pharmaceutical preparations in which the active ingredient is a 3-oxo-3,4-dihydro- 1,2,4-benzothiadiazine-1,l-dioxide, and their non-toxic alkali metal salts, and to their use in the methods for treating hypertension in mammals, including domestic mammals, such as dogs, etc.

It is well known that diuretic and/ or naturetic agents of the 3 -oX0-3,4-di|hydro-=l,2,4-benzothiadia;zine-l,l-dioxi-de compounds having a sulfamyl substituent in the benzenoid portion of the nucleus mildly reduce blood pressure in patients having hypertension. These compounds, however, have not been shown to demonstrate this activity under normotensive conditions. Moreover, authorities believe that the diuretic and/ or naturetic and anti-hypertensive actions of these compounds are so interconnected that diuretic activity is a pre-requisite for anti-hypertensive activity.

Quite unexpectedly, we have discovered that the compounds of this invention exhibit blood pressure lowering activity, despite the fact that they do not possess any diuretic activity. While we do not Wish to limit ourselves to any particular theory as to the precise mechanism as to how our compositions lower blood pressure, we do, however, desire to demonstrate the unique properties of our compositions.

From laboratory tests, it is to be found that our compositions will lower blood pressure in both normotensive and hypertensive mammals, the latter action being slow in its onset and of long duration. Likewise, our compositions will also antagonize blood pressure responses to such well known pressor agents as epinephrine, norepinephrine and angiotensin. This antagonism, it should be noted, functions without any particular specificity, but rather, the effect is general to the class of compounds functioning as pressor agents. A further property exhibited by our compositions is that they will significantly increase peripheral and coronary blood flow.

In essence, the anti-hypertensive action of our compositions does not depend upon diuresis, ganglionic blockage, or adrenergic blockade, but rather, our compositions directly affect that part of the vascular system which is deranged in hypertension, i.e.,-the peripheral vasculature. Hence, our compositions are what may be termed as true anti-hypertensives, and as such, are capable of service as valuable therapeutic agents useful for the alleviation and control of such diseases as malignant hypertension, essential hypertension, and the like, and for peripheral vascular disorders (e.g., Buergers disease, Raynauds disease, etc.), angina pectoris, and the like.

The active ingredients of our novel composition are 3-oxo-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide compounds having the below depicted structural formulae, and the non-toxic alkali metal salts thereof. In those compounds having no substituent other than hydrogen on either nitrogen in the benzothiadiazine-l,l-dioxide nucleus, the molecules possess a lactam-lactim tautomeric system wherein the tauto-mers are interconvertible by means of an alpha, gamma proton shift; the double bond in the lactim tautomer being between either the 2,3- or 3,4-positions (that is structures A, B, and C, below, wherein R is hydrogen). In those compounds having a substituent other than hydrogen on the N atom, the double bond in the lactim tautomer exists between positions 3 and 4 (that is, structure B, below, wherein R is lower 'ice alkyl) and when substitution other than hydrogen occurs on the N atom, the double bond in the lactim tautomer exists between positions 2 and 3 (that is, structure C, below, wherein R is lower alkyl). Thus, in .general, the compounds can be considered having one of the following general structures:

wherein X and Y are each representative of hydrogen, trifluoro methyl, a halogen, preferably chlorine and bromine, or a lower alkyl having 1 to 5 carbon atoms, preferably methyl and ethyl and including the straight and branched chain propyl, butyl and pentyl; and R is hydrogen or lower alkyl.

(In the remaining portion of this application, all compounds are named, as a matter of convenience, as their lactam tautomer. The named compounds and the structure of the products prepared by the processes described below must, however, be evaluated in the light of the foregoing discussion regarding the lactim-lactam tautomerism which the molecules can possess.)

Illustrative of a few of the compounds embraced by the above depicted structural formulae are:

6 chloro 3 0X0 3,4 dihydro 1,2,4 benzothiadiazine-1,1-dioxide;

7 chloro 3-oxo 3,4 dihydro 1,2,4 benzothiadiazine- 1,1-dioxide;

6,7 dichloro 3 oxo 3,4 dihydro 1,2,4 benzothiadiazine-l,1-dioxide;

2 methyl 6 trifluoromethyl 3 oxo 3,4 dihydro- 1,2,4-benzothiadiazine-1,l-dioxide; I

7 trifluoromethyl 3 oxo 3,4 dihydro 1,2,4 benzothiadiazine-1,1-dioxide;

6 methyl 3 oxo 3,4 dihydro 1,2,4 benzothiadiazine-1,1-dioxide;

7 propyl 3 oxo 3,4 dihydro 1,2,4 benzothiadiazine--1,l-dioxide;

6 isopropyl 3 oxo 3,4 dihydro 1,2,4 benzothiadiazine-1,1-dioxide;

6 chloro 7 trifiuoromethyl 3 OX0 3,4 dihydro- 1,2,4+benzothiadiazinel, l-dioxide;

6 methyl 7 bromo 3 oxo 3,4 dihydro 1,2,4-

benzothiadiazine-l,l-dioxide;

6,7 di trifluoromethyl 3 oxo 3,4 dihydro 1,2,4-

benzothiadiazine-l,l-dioxide.

As is true in any class of compositions suitable for therapeutic administration, a few are recognized as having superior pharmacological effectiveness. In general, of those active ingredient compounds which are mono-substituted in the benzenoid portion of the benzothiadiazine nucleus, it is preferred to have said substituent located at either the 6- or 7-positions; and of the compounds which are di-substituted in the said benzenoid moiety, it is preferred to have the substituents located at 6- and 7-, 6- and 8-, or the 7- and 8-positions.

Illustrative of some of the preferred active ingredient compounds of these compositions are: 6,7-dichloro-3-oxo- 3,4-dihydro-1,2,4-benzothiadiazine-1, l-dioxide; 6-trifluoromethyl-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine 1,1 dioxide; 6 chloro-7-methyl-3-oxo-3,4-dihydro-1,2,4-bemothiadiazine 1,1 dichlor0-3-oxo-3,4-dihydro-1,2,4-bemothiadiazine 1,1-dioxide; 6-trifluoromethyl-7-chloro-3-oxo- 3,4-dihydro-l,2,4-benzothiadiazine-l,l-dioxide.

The effective dosage of the compositions of this invention depends upon the severity, the stage, and the individual characteristics of each case. Generally, a dosage range of from 0.01 to about 50 mg./kg. of body weight per day would constitute the overall range, with a range of about 0.01- mg./kg. per day for the preferred compositions.

The compositions of our invention may be used in the form of pharmaceutical preparations which contain the active ingredient in admixture with a pharmaceutical carrier suitable for enteral or parenteral administration. Such preparations may be in solid forms, as for example, tablets and capsules, or in liquid forms, as for example, elixirs, emulsions and injectables.

In the formulation of pharmaceutical preparations there can be employed such substances which do not react with the active substances, as for example, water, gelatin, lactose, starches, magnesium stearate, calcium carbonate,

talc, vegetable oils, benzyl alcohols, gums, polyalky-lene glycols, and petroleum jelly.. ,The active ingredient is preferably present in the preparation in such proportions by weight that the proportion by weight of active ingredient in the formulation to be administered lies between 0.1% and 50%.

In addition to the above enumerated excipients which are incorporated into the compositions of this invention, in some instances (here again, depending upon the individual characteristics of the host, the severity of the malady being treated, potency of active ingredient, etc.) an additional active ingredient may be indicated. For example, in some instances, it may be advantageous to incorporate into the compositions of this invention a therapeutically effective quantity of a diuretic.

Satisfactory formulations are shown in the following examples which are presented for illustration only. Variant dosage forms as well as varying formulations may be prepared according to analogous procedures. The preparations may be administered once to several times per day depending upon the conditions and the response evoked.

EXAMPLE l.TABLET FORMULATION The following formulation provides for the manufacture of 1000 tablets, each containing 25 mg. of active ingredient:

G. (1) 7 chloro-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide sodium salt 25.0 (2) Lactose, U.S.P. 181.0 (3) Corn starch, U.S.P. 92.5 ('4) Magnesium stearate 1.5

A mixture of 72.5 g. of corn starch and the lactose is thoroughly granulated with a paste prepared by dissolving gm. of corn starch in.l00 ml. of hot distilled water. The resulting granulation is dried at 40-45" C. and passed thru a No. 16 mesh screen. To the dried, screened granulation is added a blended mixture of the active ingredient (l) and the magnesium stearate. The resulting mixture is thoroughly blended and then pressed into tablets of 300 mg. each.

EXAMPLE 2.CAPSULE FORMULATION The following formulation provides for the manufacture of 1000 capsules, each containing mg. of active ingredient:

G. (1) 7 chloro-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide sodium salt 25.0 (2) Lactose 273.5 (3) Magnesium stearate 1.5

The active ingredient (1) is mixed with the lactose and blended. The magnesium stearate is mixed into this blend and the resulting mixture is thoroughly blended. Hard gelatin capsules are each filled with 300 mg. of the blended mixture whereby there are obtained capsules containing 25 mg. of 7-chloro-3-oxo-3,4-dihydro-1,2,4-benzethiadiazine-l,1-dioxide.

XAMPLE 3 The following formulation provides for the manufacture of 1000 vials each containing 10 mg. of active in gredient:

(1) 7 chloro 3 oxo 3,4 dihydro 1,2,4-

benzothiadiazine-l,l-dioxide sodium salt 10.0 (2) Monobasic potassium phosphate 6.0 (3) Exsiccated sodium phosphate 12.0

(4) Water for injection, U.S.P., q.s. 1.0 liter.

Ingredients (1), (2), and (3) are dissolved in approximately of the volume of water and the resulting solution is filtered. To the resulting filtrate is added sufficient water to make a 1000 ml. volume. The solution is sterile filtered, and one milliliter portions of the so-prepared solution are aseptically filled into 2 ml. vials, and then lyophilized. After the lyophilized cake is dry, the vials are aseptically stoppered with rubber plugs and sealed.

As some of the active ingredient compounds are novel, there is embraced within the scope of this invention such novel compounds as are depicted and defined below. (Again it should be noted that although the below novel compounds are defined in their lactam form, the lactim forms are also embraced.)

and their non-toxic alkali, metal salts, wherein X is a member of the group consisting of trifiuoromethyl, lower alkyl and halogen, said member being attached to one of the benzenoid carbon atoms of the group consisting of positions 6- and 7-; Y is a member of the group consisting of hydrogen, trifluoromethyl, lower alkyl and halogen, said member being attached to the benzenoid carbon atoms of the group consisting of positions 6-, 7-, and 8-, with the proviso that X is other than halogen when Y is hydrogen.

The novel 3 oxo 3,4 dihydro 1,2,4 benzothiadiazine-1,1-dioxides of this invention can be prepared by heating a mixture of a selected o-sulfamylaniline compound and urea at a temperature of between about 225 C. It is preferred to employ the reactants in the ratio of about 1 part of the selected o-sulfamylaniline compound to two parts of urea, although an excess of two equivalents of urea can be employed without harmful effects. Heating of the reactants is continued until the mixture liquefies at which time ammonia gas is given off and thereafter the mixture resolidifies. The so-produced 3 0x0 3,4 dihydro 1,2,4 benzothiadiazine- 1,1-dioxide is then dissolved in a suitable solvent (e.g. water), filtered and the product precipitated by the addition of acid. Purification advantageously is effected by crystallization from either water or aqueous alcohol.

In general, the above mentioned o-sulfamylaniline starting materials are compounds having the structural formula:

X NHz Y S O zNHz said X and Y radicals being as defined above.

Certain of these -o-sulfamylaniline compounds may be prepared by chlorosulfonating the appropriate aniline compounds in the presence of an alkali metal halide to form the corresponding o-chlorosulfonyl halide according to procedures well-known to those skilled in the art. These compounds are then treated with ammonia to form the desired starting compound. In instances wherein the specific X- and Y-substituted aniline compounds are not known, they may readily be prepared by procedures analogous to those utilized for the known anilines.

Another, and more general method for preparing the above depicted o-sulfamylaniline starting compounds is by treating an approximately X- and Y-substituted o-nitrochlorobenzene (I) with a mixture containing thiourea, benzyl chloride and an alkali to yield a benzylthio compound (II) which compound is then successively treated with (a) chlorine in aqueous acetic acid, and then (b) ammonia, to yield the appropriate nitrosulfonarnide (III). The nitrosulfonamide is reduced with iron in an ammonium chloride solution to yield the desired substituted o-sulfamylaniline. This series of reactions may be illus- In general, if a particular o-nitrochlorobenzene (I) is not known, it may be prepared by any of the usually well-known procedures.

The alkali metal salts of the benzothiadiazine-1,1-di oxide compounds of this invention can be prepared by dissolving the selected compound in an equimolar aqueous or alcoholic solution of the alkali metal hydroxide, and, if desired, isolating the salt by evaporating the solvent. Any of the conventional alkali metal salts, such as sodium, potassium, lithium or the like can be prepared by this method or by other methods known to those skilled in the art.

The following examples will serve to further exemplify and illustrate the nature of these various reactions, and to further demonstrate the scope of the various groups which may be present in a particular position. These examples, however, are not intended and should not be construed in any Way so as to limit the scope of the present invention, as the scope is delineated by the appended claims.

EXAMPLE 4.--7-CHLORO-3-OXO-3,4-DIHYDRO- 1,2,4-BENZOTHIADIAZINE-l,l-DIOXIDE A. Z-benzylthi-4-chl0r0-nitr0benzene A mixture containing 63 g. of benzyl chloride, 38 g. of thiourea and 3 drops of concentrated ammonium hydroxide solution in 250 ml. of 95% ethanol is refluxed for 3 hours. To this refluxed mixture is added a solution containing 96 g. of 2,4-dichloro-nitrobenzene in 200 ml. of ethanol, and the resulting mixture is brought to reflux temperature. A solution of 70 g. of potassium hydroxide in 500 ml. of ethanol is added to the reflux mixture (in a dropwise fashion) and the resulting reaction mixture is refluxed for 2 hours, cooled and filtered. The filtered product, 2-benzylthio-4-chloro-nitrobenzene, is washed with aqueous ethanol and dried.

B. 2-nitr0-5-chloro-benzenesulfonamide Chlorine gas is bubbled thru a suspension containing 50 g. of 2-benzylthio-4-chloro-nitrobenzene in 1000 m1. of 33% aqueous acetic acid (maintained at a temperature range of about 05 C.) for 2 hours, to yield a colored, oil-like substance. The oil-like substance is extracted with chloroform (3 x 300 ml.) and the chloroform extracts washed with water, and dried over sodium sulfate, and filtered. The chloroform filtrate is evaporated, yielding a residue which is then treated with 400 ml. of liquid ammonia. The excess of ammonia is allowed to evaporate and the solid residue is triturated with hexane to yield a solid, 2-nitro-S-chloro-benzenesulfonamide, which is further triturated with water, filtered, dried and recrystallized from methanol-water.

C. 2-amin0-5-chlono-benzenesulfonamide To a refluxing reaction mixture containing 4.4 g. of ammonium chloride, 18 ml. of methanol, 9 ml. of water and 3.0 g. of 2-nitro-5-chloro-benzenesulfonamide is added (in a portion-wise fashion over a period of 1.5 hours) 4.4 g. of iron filings. The resulting reflux reaction is continued for 1.5 hours. The resulting mixture is filtered, and the filtrate concentrated to dryness. The resulting residue is triturated with 15 ml. of water to yield 2-amino-5-chloro-benzenesulfonamide which is filtered and recrystallized from methanol-water.

D. 7-chlor0-3-oxo-3,4-dihydr0-1,2,4-benz0thiadiazine-I ,1 -di oxide A mixture containing 6 g. of Z-amino-S-chloro-benzenesulfonamide and 3.5 g. of urea is heated at C. for 1 hour. During this period the mixture liquifies with evolution of ammonia and solidification occurs. The solid is cooled and dissolved in hot water, filtered and the filtrate is acidified with hydrochloric acid to yield crude 7-chloro-3-oxo-3,4-dihydro-l,2,4-benzothiadiazine-l,1-dioxide, which is then crystallized from aqueous ethanol.

As is apparent to one skilled in the art, by replacing the 2,4-dichloro-nitrobenzene of Example 4 with other appropriately substituted chloro-nitrobenzenes the production of other novel 3-oxo-3,4-dihydro-1,2,4-benzothiadiazines may be eifected by following substantially the procedures described in Example 4.

Therefore, by replacing the Z-chloro-nitrobenzene of part A of Example 4 with the compounds enumerated below in group A and by following substantially the procedures outlined in parts A, B and C of said example there are produced, respectively, the corresponding compounds enumerated below in group B. By substituting the 2-arnino-5-chloro-benzcnesulfonamide of part D of Example 4 with the compounds of group B and by following substantially the procedure described in part D, there are produced, respectively, the corresponding compounds enumerated below in group C.

GROUP A GROUP B (1 2-amino-5-methyl-benzenesulfonamide;

(2) 2-amino-4-methyl-benzenesulfonamide;

(3 2-arnino-S-trifiuorornethyl-benzenesulfonamide;

(4) 2-amino-4-trifluoromethyl-benzenesulfonamide;

(5 Z-amino-5-chloro-benzenesulfonamide;

( 6) 2-a-mino-4,5-dimethyl-benzenesulfonamide;

(7) 2-amino-4-methyl-5-trifluoromethyl-benzenesulfonamide;

(8) 2-amino-4-methyl-5-chloro-benzenesulfonamide;

(9) Z-amino-S-chloro-6-methyl-benzenesulfonamide;

( 10) 2-amino-4,5-ditrifiuoromethyl-benzenesulfonamide;

(1 1) 2-amino-4-trifiuoromethyl-S-methyl-benzenesulfonamide;

( 12) 2-amino-4-trifluoromethyl-S-chloro-benzenesulfonamide;

( 13 2-amino-4,5-dichloro-benzenesu1fonamide;

( 14) 2-amino-4-chloro-S-methyl-benzenesulfonamide;

(15 2-amino-4-ch1oro-5-trifluoromethyl-benzenesulfonamide;

( 16) 2-amino-5 ,6-dichloro-benzenesulfonamide;

( 17) 2-amino-4-chloro-6-trifluoromethyl-benzenesulfonamide.

GROUP C 1 7-methyl-3 -oxo-3 ,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide;

(2) 6-methyl-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide;

(3 7-trifluoromethy1-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

(4) 6-trifiuoromethyl-3-0xo-3 ,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

(5) 7-chloro-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide; I

(6) 6,7-di-methy1-3-oxo-3 ,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

(7) 6-met'hyl-7-trifiuoromethyl3 -oxo-3 ,4-dihydro-1,2,4-

benzothiadiazine-l,l-dioxide;

(8) 6-methyl-7-chloro-3 -oxo-3 ,4-dihydro-1,2,4-benzothiadiazine-1,1-di0xide;

(9) 7-chloro-8-methyl-3 -oxo-3 ,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

( 10) 6,7-ditrifluoromethyl-3 -oxo-3 ,4-dihydro-1,2,4-benzothiadiazine-l, l-dioxide;

(1 1 6-trifiuoromethyl-7-methyl-3-oXo-3,4-dihydro-1 ,2,4-

benzothiadiazine-l,l-dioxide;

( 12) 6-trif1uoromethyl-7-chloro-3 -oxo-3,4-dihydro-1,2,4-

benzothiadiazine-l ,1-dioxide;

( 13 6,7-dichloro-3-oxo-3,4-dihydro-1,2,4-benzothi.a-

cliazine-1,1-dioxide;

( 14) 6-ch1oro-7-methyl-3 -oxo-3 ,4-dihydro-1,2,4-benzothiadiazine-1,1dioxide;

( 15) 6-chlo'ro-7-trifiuoromethyl-3 -oxo-3 ,4-dihydro-1,2,4-

benzothiadiazine-1,1-dioxide;

(16) 7,8-dich1oro-3 -oxo-3 ,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

( 17 6-chloro-8-trifluoromethyl-3 -oxo-3 ,4-dihydro-1,2,4-

benzothiadiazine-l,l-dioxide.

EXAMPLE 5.SODIUM SALT OF 7-CHLORO-3OXO- 3,4-DIHYDRO-l,2,4 BENZOTHIADIAZINE 1,1- DIOXIDE.

7-ch1oro-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine 1,1- dioxide as described in Example 4 is dissolved in alcoholic sodium hydroxide and the solution is then evaporated in vacuo to yield the sodium salt of 7-ch1oro-3-oxo-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide.

While the above examples describe the preparation of certain illustrative compounds of this invention and certain specific dosage forms suitable for therapeutic administration, it is to be understood that the invention is not to be considered as limited to these specific reaction conditions described for the preparation of the compounds or by the specific ingredients included in the pharmaceutical preparations but is understood to embrace variations and modifications falling within the scope of the appended claims.

We claim:

1. 6,7-difiuoromethyl-3-oxo-3,4-dihydro 1,2,4 benzothiadiazine-1,1-dioxide.

2. A method of treating hypertension in mammals which comprises administering to a mammal a pharmaceutical preparation containing a therapeutically effective antihypertensive dose of 3-oxo-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide selected from the group having the structural formulae:

N 0 0 o o and their non-toxic alkali metal salts wherein X is a member of the group consisting of trifluoromethyl, lower alkyl and halogen, said member being attached to one of the benzenoid carbon atoms of the group consisting of positions 6- and 7-; Y is a member of the group consisting of hydrogen, trifluoromethyl, lower alkyl and halogen, said member being attached to the benzenoid carbon atoms of the group consisting of positions 6-, 7-, and 8-, and R is a member of the group consisting of hydrogen and lower alkyl.

3. A method of claim 2, wherein the total daily dose of the 3-oxo-3,4-dihydro-l,2,4-benzothiadiazine-1,1 dioxide compound is in the range of about 0.1-5 mgm./ kg. of body Weight.

4.' A method of claim 2, wherein X is halogen, Y is hydrogen and R is hydrogen.

5. A method of claim 2, wherein X is halogen, Y is trifluoromethyl and R is hydrogen.

6. A method of claim 2, wherein X is trifluoromethyl, Y is hydrogen and R is hydrogen.

7. A method of claim 2, wherein X is trifiuoromethyl, Y is halogen and R is hydrogen.

References Cited by the Examiner UNITED STATES PATENTS 2,910,474 10/1959 Novello 260--243 FOREIGN PATENTS 1,067,028 10/1959 Germany.

36,956 3/ 1959. Luxembourg.

OTHER REFERENCES Scott: J. Chem. Soc., vol, 123, pp. 319l3202 (1923). Yale et al.: J. Med. and Pharm. Chem., vol. I, No. 2, pages 121-131 (1959).

NICHOLAS S. RIZZO, Primary Examiner.

IRVING MARCUS, Examiner. 

2. A METHOD OF TREATING HYPERTENSION IN MAMMALS WHICH COMPRISES ADMINISTERING TO A MAMMAL A PHARMACEUTICAL PREPARATION CONTAINING A THERAPEUTICALLY EFFECTIVE ANTIHYPERTENSIVE DOSE OF 3-OXO-3,4-DIHYDRO-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE SELECTED FROM THE GROUP HAVING THE STRUCTURAL FORMULAE: 